By Gia Nevel, PMHNP
Ketamine is a dissociative anesthetic, also classified as a Rapid Acting Antidepressant Drug
(RAAD). Ketamine has emerged as a groundbreaking therapy for treatment-resistant depression
due to its unique ability to alleviate symptoms of depression, post-traumatic stress disorder, and
other mental health conditions rapidly. The exact mechanisms of ketamine are complex and still
being investigated. Yale University School of Medicine has been a pioneer in ketamine research,
identifying applications for depression, post-traumatic stress disorder, and other conditions.
Ketamine works on multiple cellular pathways in the body. However, the most significant appears
to be through the neurotransmitter glutamate.
Glutamate Transmission:
Ketamine primarily affects the glutamatergic system, which involves neurons that use glutamate.
Glutamate is an excitatory neurotransmitter that transmits signals between neurons in the brain.
It can be considered an accelerator pedal for the brain, speeding up information flow. Glutamate
affects mood, learning, and memory. Ketamine balances glutamate signals, which enhances
cellular communication. Typical antidepressants target other neurotransmitters, such as
serotonin and norepinephrine.
Brain Circuitry Changes:
In patients with depression, post-traumatic stress disorder (PTSD), and other conditions;
neurons in important areas of the brain involved in emotion and attention become disconnected.
The prefrontal cortex (PFC), amygdala, and hippocampus are key regions affected. This can lead
to further dysregulation, self-rumination, and negative thinking.
Ketamine fortifies and increases neural connections in the PFC, amygdala, and hippocampus to
improve cognition and mood; while dampening the dysfunctional overactive circuits. This is
thought to alleviate symptoms and boost the brain’s resilience against future stressors.
Antidepressants increase the number of new neurons after several weeks. Other therapies such
as psychotherapy, exercise, and Electroconvulsive therapy (ECT) also cause neuron growth at a
similar delayed rate. Remarkably, ketamine speeds up this process, rejuvenating these cells and
causing new growth in hours to days.1
Receptor Interactions and Downstream Effects
By influencing what receptors glutamate binds to, ketamine causes a cascade of downstream
changes to signaling pathways and neuron plasticity. Ketamine’s ability to work throughout the
brain on multiple fronts creates a rapid and global effect unlike any other antidepressant
available. Ketamine also indirectly supports the brain’s ability to heal itself.
Below is an overview of just some ways ketamine does this:
NMDA Receptor Blocking: Ketamine temporarily blocks NMDA receptors. This alters glutamate-
related signaling, boosting communication in the brain.
AMPA Receptor Activation: By blocking glutamate binding to NMDA receptors, ketamine
indirectly makes glutamate more available to bind to other receptors, such as AMPA. Activation
of the AMPA receptor strengthens the connections between neurons,
improving mood and reducing depressive symptoms.
BDNF Boost: Brain-derived neurotrophic Factor (BDNF) is like the brain’s fertilizer, nurturing and
growing the connections between brain cells. Ketamine increases BDNF through AMPA receptor
activation, glutamate, and other pathways.
mTOR Activation: mTOR is an enzyme involved in cell growth and protein synthesis. It supports
the formation and strengthening of synapses or neuron connections in the brain, improving
mood and cognition. Ketamine activates the mTOR pathway, causing rapid antidepressant
effects and increasing BDNF. No other antidepressants are known to activate mTOR.4
Brain Inflammation: Inflammation in the brain
has been linked to chronic stress, anxiety, and depression. Ketamine has anti-inflammatory
properties, diminishing the activity of inflammatory cells like cytokines. Additionally, by
improving mood and reducing anxiety, ketamine may indirectly reduce stress, further
decreasing inflammation.
A catalyst for change:
Through chemical, behavioral, and circuitry changes, Ketamine supports
adaptability. Our brains continuously adapt in response to our thinking and
experiences, which, in turn, influence how we respond to our environment. The
more frequently a particular thought or habit occurs, the more swift and automatic its
corresponding neural connection becomes. When we modify our thinking patterns and
behaviors, these neural pathways adjust, reshaping our thoughts and behaviors in a feedback
loop. Ketamine amplifies this adaptability, acting as a booster for our brain’s flexibility.
Seeing the World Differently: Ketamine can have dissociative effects that
temporarily alter perceptions and consciousness. This “reset” can offer a
fresh perspective, helping individuals view their problems in
a new light and contributing towards long-lasting benefits. Read more about this here.
Ketamine Creates New Connections
Depression and other mental health conditions can represent a disconnection from the world,
loved ones, and even within our brains. Ketamine reconnects these pathways, acting on the
brain’s communication systems to rejuvenate and refresh its circuits. It offers a promising
avenue for those struggling with mental health to rediscover their connection to the world
around them.
If you or your loved one are suffering from depression, ketamine therapy may be a great next step for you. Feel free to call Kure Medical or your local ketamine center to learn more about ketamine infusion therapy. If this is an emergency, please call the National Mental Health Hotline: 988 or call the National Emergency Hotline: 911
Disclaimer: This blog is for informational purposes only and does not constitute medical advice. Please consult with a healthcare professional for personalized recommendations and guidance regarding ketamine therapy.
